Heterozygosity for a hypomorphic polβ mutation reduces the expansion frequency in a mouse model of the fragile x-related disorders

Lokanga, Rachel Adihe; Senejani, Alireza Ghodsi; Sweasy, Joann Balazs; Usdin, Karen

Heterozygosity for a hypomorphic polβ mutation reduces the expansion frequency in a mouse model of the fragile x-related disorders

Journal Article

2015

Journal Title

PLOS Genetics

Link to Journal

http://journals.plos.org/plosgenetics

Publisher

Public Library of Science

Publisher

University of Cape Town

Department

Department of Molecular and Cell Biology

Faculty

Faculty of Science

License

http://creativecommons.org/licenses/by/4.0

Abstract

Author Summary Unstable microsatellites are responsible for a number of debilitating human diseases known as the Repeat Expansion Diseases. The unstable microsatellites, which consist of tandem arrays of short repeat units, are prone to increase in length (expand) on intergenerational transmission and during the lifetime of the individual. Unlike the typical microsatellite instability seen in disorders like Lynch syndrome that arise from mutations in mismatch repair (MMR) genes, expansions of these microsatellites are abolished when MMR is lost. However, how MMR, which normally protects the genome against microsatellite instability, actually promotes microsatellite expansions in these diseases is unknown. There is evidence to suggest that a second DNA repair process, base excision repair (BER), may be involved, but whether the nicks generated early in the BER-process are subverted by an MMR-dependent pathway that generates expansions or whether some MMR proteins contribute to a BER-based expansion process is unclear. Here we show that a mutation that reduces the activity of Polβ, an essential BER enzyme, also reduces the expansion frequency. Since Polβ is essential for key events in BER downstream of the generation of nicks, our data favor a model in which expansions occur via a BER-dependent pathway in which MMR participates.